An inflammatory response is known as a protective response of living organism for rehabilitating the structures and functions of tissues damaged by infection, trauma, etc. Mobilization of leukocytes to a focus of inflammation is critical for the rapid resolution of infections and restoration of tissue damages resulting from a variety of injuries. However, a misdirected or prolonged inflammatory response causes damage to the body's tissues or diseases. For example, inflammatory diseases are caused by bacterial or viral infection, e.g., cerebrospinal meningitis, enteritis, dermatitis, uveitis, encephalitis, or adult respiratory distress syndrome, or non-infectious factors, e.g., trauma, autoimmune diseases, or organ transplantation rejection. Inflammatory diseases are classified into acute and chronic inflammatory diseases according to symptoms or pathological features. Acute inflammation such as allergy or bacterial/viral infection is manifested as local signs such as a change in bloodstream, blood vessel size, and vascular permeability, and the recruitment of leukocytes. In contrast, a main pathological feature of chronic inflammation such as rheumatoid arthritis, artherosclerosis, chronic kidney infection, or hepatocirrhosis is a continuous emigration of macrophages, lymphocytes, or plasma cells into foci of inflammation due to recurrence of inflammatory factors, thereby causing a long-lasting inflammatory response.
Pro-inflammatory mediators expressed at the sites of inflammation, such as cytokines, chemokines, reactive oxygen intermediates, cycloxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), matrix metalloproteinase (MMP), play a critical role in generation and maintenance of inflammatory reaction. It is known that the expressions of such pro-inflammatory mediators are controlled by transcription factors, such as NF-κB (nuclear factor κB), STAT3 (signal transducer and activator of transcription 3), AP-1 (activator protein1), HIF-1a (hypoxia-inducible factor 1a).
Cancer cells induced by carcinogens proliferate rapidly relative to normal cells, thereby forming tumor masses, invading surrounding tissues, and interfering with normal body functions. Cancer cells bring nutrients and oxygen by inducing angiogenesis, and metastasis thereof is also caused by angiogenesis. Although cancer cells grow infinitely at specific sites, they can also leave the sites from which they originated, migrate to and grow in new sites, whose process is called “metastasis”. Metastasis involve several key steps: conversion of cancer cells to migratory mesenchymal cells, dissociation of the mesenchymal cells from the original tumor sites, invasion into and spread through surrounding connective tissues and capillary vessels, migration through blood vessels, escape from the blood vessels, migration through connective tissues, and proliferation in secondary sites.
Meanwhile, NF-κB has a homodimer form or a heterodimer form, which is derived from the 5 subunits, i.e., RelA (p65), c-Rel, RelB, p50 (NF-κB1), and p52 (NF-κB2). All the subunits share the DNA binding sites, the dimerization sites, the IκB (inhibitory KB) binding sites. In an inactivated state, NF-κB binds to IκB in the cytoplasm, which inhibits the translocation of NF-κB into the nucleus and the binding to target gene promoters. When NF-κB is activated by pro-inflammatory cytokines (e.g., TNFα, IL-1, etc.); physical stimuli (e.g., UV, radiation, etc.); pathogenic organisms and lipopolysaccharides (LPSs) derived therefrom; double-strand RNAs, etc., NF-κB dissociates from IκB to enter the nucleus and then binds to κB elements, thereby inducing the transcriptions of about 400 genes responsible for inflammation, immune response, tumor cell division, invasion, metastasis, angiogenesis, tolerance to anticancer agents, tolerance to radioactivity, etc. (Sethi G, Shanmugam M K, Ramachandrasn L, Kumar A P, Vinay Tergaonkar V. 2012. Multifaceted link between cancer and inflammation. Biosci. Rep. 32:1). Therefore, NF-κB is a transcription factor that plays a pivotal role in not only the control of pro-inflammatory cytokine expression but also the growth and/or metastasis of cancer cells.